The present invention relates to an O/W emulsion composition in which fluorometholone or clobetasone butyrate is highly soluble in body fluids such as blood and lachrymal fluid and having excellent property of keeping the solubility and concentration of fluorometholone or clobetasone butyrate contained in the composition.
Fluorometholone and clobetasone butyrate are synthetic adrenocortical hormones having a strong anti-inflammatory activity. Fluorometholone is effective in the treatment of the inflammatory diseases of outer ocular area and anterior segment of the eye, and clobetasone butyrate is effective in the treatment of the inflammatory diseases of eyes and also those of the skin. It is expected that these drugs are also effective in the treatment of the local and generalized inflammatory diseases other than those described above. However, because these drugs are hardly soluble in water, it is impossible to dispense these drugs in the form of ordinary aqueous preparations such as eye drops and parenteral injections. Therefore, in the ophthalmic field, fluorometholone and clobetasone butyrate have been each used in the form of an aqueous suspension which is prepared by finely pulverizing the crystals thereof and dispersing and suspending a suitable amount of the fine crystals in an aqueous liquid for eye drops. However, because these drugs are hardly soluble in water, the degree of dissolution of these drugs in the form of crystalline particles, contained in the aqueous suspension, into the lachrymal fluid is low and, accordingly, the bioavailability is extremely low.
It is known that the bioavailability of a hardly soluble drug generally depends on the solubility of the drug in water. For example, when such a hardly soluble drug is administered in the form of an oral solid preparation, the rate of release of the drug from the preparation thereof and dissolution of the drug are the rate-controlling step for the absorption of the drug (see xe2x80x9cIyakuhin no Bioavailability to Seibutsugaku-teki Dotosei Shikenxe2x80x9dwritten by. Hiroyasu Ogata and Masayoshi Samejima and published by Yakugyo Jiho, inc.). In addition, when such a hardly soluble drug in the form of its suspension is applied to the eyes, transition of the drug into the eye tissue depends on the dissolution rate of the drug from the crystalline particles diluted with the lachrymal fluid [J. Pharm. Sci., 64 (6), 931-936 (1975)]. Namely, the bioavailability can be improved if the concentration of the administered, hardly soluble drug in the body fluids could be increased.
WO 97/05882 discloses that an O/W emulsion comprising fluorometholone or clobetasone butyrate as a drug, a phospholipid, a liquid paraffin and water improves the solubility of the drug in the lachrymal fluid to improve transfer of the drug into the eye tissue. However, this publication is silent on the influence of the additives on the nature of the composition to improve the solubility of fluorometholone or clobetasone butyrate in the lachrymal fluid, and also on the additives used for improving the solubility. This publication is also silent on the stability of the dissolution concentration of these drugs in the lachrymal fluid and of the concentration of these drugs in the composition during the storage. The inventors examined the storability of the emulsion preparations to find that both fluorometholone and clobetasone butyrate were crystallized during the storage and the ability of the composition to improve the solubility of these drugs in the lachrymal fluid were lowered.
As for the techniques of improving the stability of such a kind of emulsion, various emulsions comprising a water-soluble polymer were disclosed [see WO 93/15736, WO 96/40051, Japanese Patent Unexamined Published Application (hereinafter referred to as xe2x80x9cJ. P. KOKAIxe2x80x9d) No. Sho 53-121920, J. Soc. Cosmet. Chem., 37, 329-350 (1986), J. SCCJ, 27 (3), 206-215 (1993), and Int. J. Pharm., 140 (1), 97-109 (1996)]. However, these prior techniques are silent on the solubility of the drug in the body fluids and also on the improvement in the stability of the concentration of the drug contained in the composition (hereinafter referred to as xe2x80x9cdrug concentrationxe2x80x9d). J. P. KOKAI No. Hei 5-186333 discloses that an ophthalmic O/W emulsion composition comprising a drug, an oil, a phospholipid and an amphoteric surfactant is capable of keeping the average particle diameter and the drug concentration thereof during the storage.
The present invention has been developed for the purposes of improving the solubility of the conventional, hardly water-soluble drug in the body fluid and the stability of the improved solubility of the drugs in the body fluids. The object of the present invention is to provide a novel composition containing fluorometholone or clobetasone butyrate highly soluble in body fluids such as blood and lachrymal fluid and having excellent property of keeping the solubility of these drugs into body fluids and concentration of fluorometholone or clobetasone butyrate contained in the composition. After intensive investigations made for the purpose of attaining the above-described object, the inventors have found that an O/W emulsion composition containing fluorometholone or clobetasone butyrate, a phospholipid, an oil, a nonionic water-soluble cellulose derivative and water shows a high solubility of fluorometholone or clobetasone butyrate in the body fluids and such a high solubility thereof and the concentration of fluorometholone or clobetasone butyrate contained in the composition can be kept stable during the storage. The inventors have further found that when at least one member of the group consisting of chelating agents, polycarboxylic acid compounds and pharmaceutically acceptable salts thereof is incorporated into the emulsion composition, the solubility of fluorometholone or clobetasone butyrate in the body fluids and the concentration of fluorometholone or clobetasone butyrate contained in the composition can be kept stable for a far longer period of time. The present invention has been completed on the basis of these findings.
Namely, the present invention provides an O/W emulsion composition containing fluorometholone or clobetasone butyrate, a phospholipid, an oil, a non-ionic water-soluble cellulose derivative and water and, if necessary, at least one member of the group consisting of chelating agents, polycarboxylic acid compounds and pharmaceutically acceptable salts thereof. The present invention is characterized in that the solubility of fluorometholone and clobetasone butyrate in the body fluids is improved by incorporating the nonionic water-soluble cellulose derivative as an indispensable component. Other characteristic features of the present invention are that the solubility of fluorometholone and clobetasone butyrate in the body fluids is high and that the concentration of fluorometholone and clobetasone butyrate in the composition can be kept stable during the storage. By suitably changing the proportion of the constituents and amounts thereof, the O/W emulsion composition having a particularly high solubility of fluorometholone or clobetasone butyrate in the body fluids can be obtained, and the solubility and the concentration of fluorometholone or clobetasone butyrate contained in the composition can be kept stable for a longer period of time in the present invention. The O/W emulsion composition containing fluorometholone or clobetasone butyrate can be given to the patients by the systemic administration method or topical administration method in a suitable preparation form such as liquids for internal use, injections, ear drops, nasal drops, eye drops, aerosols or inhalations depending on the need. The O/W emulsion composition is usable for the treatment of diseases such as chronic hypoadrenocorticism, acute chronic hypoadrenocorticism, chronic articular rheumatism, ankylosing spondylitis, lupus erythematodes, systemic angitis, polymyositis, nephrosis and nephrotic syndrome, congestive heart failure, bronchial asthma, asthmatic bronchitis, allergy and intoxication caused by drugs and other chemical substances, severe infectious diseases, hemolytic anemia, leukemia, aplastic anemia, localized enteritis, tumorous colitis, fulminant hepatitis, chronic hepatitis, hepatic cirrhosis, sarcoidosis, diffuse interstitial pneumonia, post-invasion pulmonary edema, tuberculous meningitis, tuberculous pleurisy, tuberculous peritonitis, tuberculous pericarditis, encephalomyelitis, peripheral neuritis, spinal arachnoiditis, malignant lymphoma, adrenalectomy, organ and tissue transplantation, snake poison, insect poison, acute eczema, chronic eczema, contact dermatitis, autosensitization dermatitis, atopic dermatitis, neurodermatitis, dermatitis seborrhoica, hives, psoriasis and analogous diseases, anaphylactoid purpura, mucocutaneos ocular syndrome, Raynaud""s disease, pemphigus group, herpes zoster, allergic angitis and analogous diseases, inflammatory diseases of intaocular, optic nerve, orbit and ocular muscle, inflammatory diseases of outer ocular area and anterior segment of the eye (when the application of eye drops is unsuitable or insufficient in the symptomatic therapy), acute and chronic otitis media, vasomotor rhinitis, allergic rhinitis, pollenosis, progressive gangrenous rhinitis, pharyngeal catarrh and pharyngeal enema, pharyngeal polyp and nodule, esophagitis and esophageal dilation operation (aftercare), otorhinolaryngologic operation (aftercare), intractable stomatitis and glossitis, acute and chronic (recurrent) sialadenitis, anaphylactic shock, retiochoroiditis, retinal vasculitis, optic neuritis, orbital inflammatory pseudotumor, orbital apex syndrome, opthalmoplegia, inflammatory diseases of outer ocular area and anterior segment of the eye such as blepharitis, conjunctivitis, keratitis, scleritis, episcleritis, iritis, iridocyclitis, uveitis and postoperative inflammations.
The detailed description will be made below on the present invention.
The nonionic, water-soluble cellulose derivatives contained in the O/W emulsion composition (hereinafter referred to as xe2x80x9cemulsionxe2x80x9d) of the present invention are not particularly limited. They include, for example, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose and hydroxyethylmethylcellulose. The degree of substitution and viscosity grade of the nonionic, water-soluble cellulose derivative are not particularly limited. The nonionic, water-soluble cellulose derivatives having any degree of substitution and any viscosity grade are usable in the present invention. At least one of the nonionic, water-soluble cellulose derivatives is incorporated into the emulsion of the present invention.
Among those nonionic, water-soluble cellulose derivatives, methylcellulose and hydroxypropylmethylcellulose are preferred because when either of them is used, a high concentration of fluorometholone (hereinafter referred to as xe2x80x9cFLMxe2x80x9d) or clobetasone butyrate (hereinafter referred to as xe2x80x9cCBxe2x80x9d) dissolved in the body fluids can be obtained, and the dissolution concentration thereof and also the concentration of FLM or CB contained in the composition (hereinafter referred to as xe2x80x9cFLM concentrationxe2x80x9d or xe2x80x9cCB concentrationxe2x80x9d) can be kept stable for a longer period of time. Methylcellulose is the most preferred.
These nonionic, water-soluble cellulose derivatives are easily available on the market under the trade names of Metolose (registered trademark) SM-15, Metolose SM-25, Metolose SM-100, Metolose SM-400, Metolose SM-1500, Metolose SM-4000 and Metolose SM-8000 (methylcellulose; products of Shin-Etsu Chemical Co., Ltd.); TC-5E, TC-5MW, TC-5R, TC-5S, Metolose (registered trademark) 60SH-50 and Metolose 60SH-4000 (Hydroxypropylmethylcellulose 2910; Shin-Etsu Chemical Co., Ltd.); Metolose (registered trademark) 65SH-50, Metolose 65SH-400, Metolose 65SH-1500 and Metolose 65SH-4000 (Hydroxypropylmethylcellulose 2906; Shin-Etsu Chemical Co., Ltd.); SB-4, Metolose (registered trademark) 90SH-100, Metolose 90SH-400, Metolose 90SH-4000 and Metolose 90SH-30000F (Hydroxypropylmethylcellulose 2208; Shin-Etsu Chemical Co., Ltd.); FUJICHEMI HEC CF-H (hydroxyethylcellulose; Fuji Chemical Co., Ltd.); Tylose (registered trademark) H30OG4PHA (hydroxyethylcellulose; Clariant (Japan) K. K.); Shin-Etsu HPC (hydroxypropylcellulose; Shin-Etsu Chemical Co., Ltd.); and Tylopur (registered trademark) MH300G4 (hydroxyethylmethylcellulose; Clariant (Japan) K. K.).
The amount of the nonionic, water-soluble cellulose derivative used is usually 0.0005 to 5 w/v %, preferably 0.001 to 1 w/v %, more preferably 0.005 to 0.5 w/v %, and most preferably 0.025 to 0.5 w/v %. When the amount of the nonionic, water-soluble cellulose derivative used is 0.0005 w/v % or higher, the stability of the dissolution concentration of FLM or CB in the body fluids and the concentration of FLM or CB in the composition during the storage can be kept high. When the amount of the nonionic, water-soluble cellulose derivative used is 5 w/v % or less, the obtained emulsion has a low viscosity to make the administration thereof easy and a comfortable feeling is recognized when the emulsion is used as eye drops. It is preferable to use the amount of the nonionic, water-soluble cellulose derivative in the range of 0.025 to 0.5 w/v % since the obtained emulsion shows particularly high stability of the dissolution concentration of FLM or CB in the body fluids and the concentration of FLM or CB.
The chelating agents, polycarboxylic acid compounds and pharmaceutically acceptable salts thereof used in the present invention are not particularly limited. They include, for example, ethylenediamine-tetraacetic acid (EDTA), citric acid, thiomalic acid, L-glutamic acid, succinic acid, malonic acid, maleic acid, dl-malic acid, adipic acid, tartaric acid, D-tartaric acid, fumaric acid, L-aspartic acid, glycyrrhizic acid, hydroxyethylethylenediaminetriacetic acid, diethylenetriamine-pentaacetic acid and pharmaceutically acceptable salts of them, and L-cystine. At least one of the group consisting of these chelating agents, polycarboxylic acid compounds and pharmaceutically acceptable salts thereof is incorporated into the emulsion of the present invention. Among these chelating agents, polycarboxylic acid compounds and pharmaceutically acceptable salts thereof, EDTA, citric acid and pharmaceutically acceptable salts thereof, which are widely used for eye drops, are preferred.
The pharmaceutically acceptable salts of EDTA usable in the present invention are, for example, sodium edetate (disodium edetate), tetrasodium edetate (tetrasodium edetate dihydrate), tetrasodiuin edetate tetrahydrate and calcium disodium edetate. Examples of the pharmaceutically acceptable salts of citric acid usable in the present invention are sodium citrate (trisodium citrate), disodium citrate (dibasic sodium citrate), trisodium citrate, sodium dihydrogen citrate, calcium citrate, dipotassium hydrogen citrate, potassium dihydrogen citrate and tripotassium citrate monohydrate.
The chelating agent, polycarboxylic acid compound and pharmaceutically acceptable salt thereof are used each in an amount of usually 0.0001 to 0.2 w/v %, preferably 0.0004 to 0.18 w/v %, more preferably 0.0005 to 0.18 w/v %, and most preferably 0.0025 to 0.05 w/v %. When the amount of the chelating agent, polycarboxylic acid compound and pharmaceutically acceptable salt thereof is 0.0001 w/v % or higher, the dissolution concentration of each of FLM and CB in the body fluids and the stability of the concentration of FLM and CB during the storage are high. When the amount of the chelating agent, polycarboxylic acid compound and pharmaceutically acceptable salt thereof is 0.2 w/v % or less, the stability of the emulsion is high. The amount of the chelating agent, polycarboxylic acid compound and pharmaceutically acceptable salt thereof in the range of 0.0025 to 0.05 w/v % is preferable. Because the obtained emulsion shows a particularly high stability of the dissolution concentration of FLM or CB in the body fluids and of the concentration of FLM or CB during the storage. In addition, this emulsion is free from the color change and oil drop formation (or oil separation) during the storage.
The drug in the emulsion of the present invention is FLM or CB, and the concentration thereof is usually 0.001 to 0.5 w/v %, preferably 0.005 to 0.1 w/v %. When the concentration of FLM or CB is 0.001 w/v % or higher, the dissolution concentration thereof in the body fluids is high. When the concentration of FLM or CB is 0.5 w/v % or less, this drug is not easily crystallized during the storage. The concentration of FLM or CB in the range of 0.005 to 0.1 w/v % is preferred because the obtained emulsion shows a particularly high stability of the dissolution concentration of FLM or CB in the body fluids and of the concentration of FLM or CB during the storage.
The phospholipids used in the present invention are not particularly limited. They are, for example, yolk lecithin, soybean lecithin, as well as lyso-forms and hydrogenated products thereof, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, dicetyl phosphate, sphingomyelin; synthetic phospholipids such as dimyristoyl phosphatidylcholine, dip almitoyl phosphatidylcholine and distearoyl phosphatidylcholine; and mixtures of these phospholipids. At least one phospholipid selected from among the above-described group of the phospholipids is incorporated into the emulsion of the present invention.
These phospholipids are easily available on the market under the trade names of, for example, Coatsome (registered trademark) NC-10S (high purity yolk lecithin; a product of NOF Corporation), purified egg yolk lecithin (Asahi Chemical Industry Co., Ltd.), Egg yolk lecithin PL-100H, ditto PL-100E, ditto PL-100LE and ditto PC-98N (Q. P. Corporation), Powdery egg yolk lecithin (hydrogenated and purified yolk lecithin) R-27, ditto R-20 and ditto R-5 (Asahi Chemical Industry Co., Ltd.), PCS (soybean phosphatidylcholine; Nippon Fine Chemical Co., Ltd.), PCSH (hydrogenated soybean phosphatidylcholine; Nippon Fine Chemical Co., Ltd.), Coatsome (registered trademark) NC-21 (hydrogenated soybean lecithin; NOF Corporation), Egg yolk lecithin LPL-20 (Q. P. Corporation), Coatsome (registered trademark) MC-6060 (L-xcex1-dipalmitoyl phosphatidylcholine; NOF Corporation), Coatsome (registered trademark) MA-6060 (L-xcex1-dipalmitoyl phosphatidic acid; NOF Corporation), Coatsome (registered trademark) MGLS-6060 (Na salt of L-xcex1-dipalmitoyl phosphatidyl-DL-glycerol; NOF Corporation), Coatsome (registered trademark) MGLA-6060 (NH, salt of L-xcex1-dipalmitoyl phosphatidyl-DL-glycerol; NOF Corporation), Sphingolipid CB-1 (a sphingolipid; Q. P. Corporation), etc.
When FLM is incorporated as the drug into the emulsion of the present invention, the amount of the phospholipid used is usually 10 to 150 parts by weight, preferably 20 to 100 parts by weight and more preferably 40 to 100 parts by weight, per one part by weight of FLM. In case the phospholipid is contained in the emulsion in an amount of at least 10 parts by weight per one part by weight of FLM, FLM is not easily crystallized during the storage. Also, by using the phospholipid in an amount of not larger than 150 parts by weight per one part by weight of FLM, the dissolution concentration of FLM in the body fluids is high. It is preferred to use phospholipid in an amount in the range of 40 to 100 parts by weight per one part by weight of FLM because the obtained emulsion has a particularly high stability of the dissolution concentration of FLM in the body fluids and of the concentration of FLM in the composition during the storage.
When CB is incorporated as the drug into the emulsion of the present invention, the amount of the phospholipid used is usually 5 to 100 parts by weight, preferably 10 to 80 parts by, per one part by weight of CB. By using the phospholipid in an amount of at least 5 parts by weight per one part by weight of CB, CB is not easily crystallized during the storage. Also, by using the phospholipid in an amount of not larger than 100 parts by weight per one part by weight of CB, the dissolution concentration of CB in the body fluids is high. It is preferable to use phospholipid in an amount in the range of 10 to 80 parts by weight per one part by weight of CB because the obtained emulsion has a particularly high stability of the dissolution concentration of CB in the body fluids and of the concentration of CB in the composition during the storage.
An emulsifying adjuvant may be added to the phospholipids. Examples of the emulsifying adjuvant include sterols such as cholesterol; aliphatic amines such as stearylamine; saturated and unsaturated fatty acids such as stearic acid, palmitic acid, myristic acid, linoleic acid and oleic acid; and pharmaceutically acceptable salts (such as sodium salts and potassium salts) of them. Although the amount of the emulsifying adjuvant is not particularly limited, usually it is not larger than 0.2 part by weight per one part by weight of the phospholipid. The oil used in the present invention is not particularly limited. The oils are, for example, vegetable oils such as soybean oil, sesame oil, corn oil, peanut oil, olive oil, safflower oil, jojoba oil, cotton seed oil and rapeseed oil; oils derived from animal oils and fats such as squalane; mono-, di- and triglycerides of fatty acids having 6 to 18 carbon atoms (such as caproic acid, stearic acid, palmitic acid, myristic acid and linoleic acid) such as glycerol tricaprylate and tricaprylin and mixtures of them; mineral oils such as liquid paraffin and light liquid paraffin; silicone oil; and fatty acid esters. The viscosity and specific gravity of these oils are not particularly limited. The oils having any viscosity and specific gravity are usable in the present invention. At least one of the oils of the above-described group is incorporated into the emulsion of the present invention.
These oils are easily available on the market under the trade names of Purified soybean oil (Showa Sangyo Co., Ltd.), Purified olive oil (Showa Sangyo Co., Ltd.), NIKKOL Safflower Oil (Nikko Chemicals Co., Ltd.), NIKKOL Jojoba Oil E (Nikko Chemicals Co., Ltd.), NIKKOL Triester F-810 (medium-length chain fatty acid triglycerides; Nikko Chemicals Co., Ltd.), Panasate. 810 (medium-length chain fatty acid triglycerides; NOF Corporation), NIKKOL Trifat P-52 (hydrogenated palm oil fatty acid triglycerides; Nikko Chemicals Co., Ltd.), NIKKOL MGS-A (glycerol monostearate; Nikko Chemicals Co., Ltd.), NIKKOL IPM-EX (isopropyl myristate; Nikko Chemicals Co., Ltd.), NIKKOL IPP (isopropyl palmitate; Nikko Chemicals Co., Ltd.), Toray Dow Corning Silicone SH20OC-100cs (Toray Dow Corning Silicone Corp., Light Liquid Paraffin No. 70-S, Liquid Paraffin No. 150-S, Liquid Paraffin No. 260-S and Liquid Paraffin No. 350-S (Sanko Chemical Industry Co. Ltd.).
Among these oils, the liquid paraffin is preferred because the color change of the emulsion during the storage is only slight when it is used.
When FLM is incorporated as the active ingredient, the amount of the oil used is usually 0.5 to 20 parts by weight, preferably 1 to 10 parts by weight, per one part by weight of the phospholipid, and the oil concentration in the emulsion is preferably not higher than 25 w/v %. When the amount of the oil used together with FLM is in the range of 0.5 to 20 parts by weight per one part by weight of the phospholipid, the stability of the emulsion during the storage is high. When the amount of the oil used together with FLM is at least 0.5% by weight per one part by weight of the phospholipid, the color change during the storage is only slight. The oil concentration in the emulsion is preferably 25 w/v % or below because an emulsion having a low viscosity can be obtained, which can be easily administered, and when the emulsion is used as eye drops, a comfortable feeling is realized upon the application.
When CB is incorporated. as the active ingredient, the amount of the oil used is usually 0.5 to 80 parts by weight, preferably 0.5 to 50 parts by, per one part by weight of the phospholipid, and the oil concentration in the emulsion is preferably not higher than 25 w/v %. When the amount of the oil used together with CB is in the range of 0.5 to 80 parts by weight per one part by weight of the phospholipid, the stability of the emulsion during the storage is high and oil drops are not formed during the storage. When the amount of the oil used together with CB is at least 0.5 % by weight per one part by weight of the phospholipid, the color change during the storage is only slight. The oil concentration in the emulsion is preferably 25 w/v % or below because an emulsion having a low viscosity can be obtained, which can be easily administered, and when the emulsion is used as eye drops, a comfortable feeling is realized upon the application.
In preparing the emulsion of the present invention, additives may be added to the indispensable components, i. e. water, oil or phospholipid so far as the effect of the present invention is not impaired. The additives are isotonicity agents such as sugars, e.g. xylitol, mannitol, sorbitol and glucose, and polyhydric alcohols, e.g. propylene glycol and glycerol; pH adjusting agents such as sodium hydroxide and hydrochloric acid; preservatives such as parabens, e. g. methyl p-hydroxybenzoate and propyl p-hydroxybenzoate, sorbic acid and pharmaceutically acceptable salts thereof, benzyl alcohol, phenethyl alcohol, benzethonium chloride, benzalkonium chloride, chlorhexidine gluconate, hydroxyquinoline sulfate, chlorobutanol and thimerosal; thickening agents such as synthetic polymers, e.g. polyvinylpyrrolidone, polyvinyl alcohol and sodium polyacrylate, high-molecular protein materials, e.g. gelatin, and polysaccharides, e.g. dextran, carrageenan, sodium chondroitin sulfate, xantham gum, gum arabic, Karaya gum and locust bean gum; antioxidants such as ascorbic acid, sodium hydrogensulfite, sodium thioglycolate and xcex1-thioglycerol; and buffering agents such as acetic acid, phosphoric acid and pharmaceutically acceptable salts of them, monoethanolamine, triethanolamine, boric acid, borax, sodium carbonate, sodium hydrogen carbonate, aminoethyl sulfonic acid, xcex5-aminocaproic acid, sodium chloride and potassium chloride.
Further, at least one stabilizer selected from the group consisting of amino acids and pharmaceutically acceptable salts thereof, tocopherol and derivatives thereof and sucrose fatty acid esters, can be added to one of the indispensable components, i. e. water, oil and phospholipid, of the present invention.
Examples of amino acids usable in the present invention include cysteine, histidine, pharmaceutically acceptable salts (such as hydrochlorides) of them, methionine, phenylalanine, serine and the like.
Examples of the tocopherol derivatives usable in the present invention include tocopherol acetate, tocopherol nicotinate, tocopherol succinate and the like.
The pH of the emulsion of the present invention is usually controlled in the range of 3 to 10. From the viewpoint of the irritation, the pH range is preferably 5 to 9. When the emulsion is used as eye drops, pH range is preferably 5.5 to 8.0.
The emulsion of the present invention can be sterilized by the filtration sterilization method with a membrane or by the heating sterilization method.
The emulsion of the present invention can be filled into a plastic eye drop bottle to use it as eye drops. In order to stably store the emulsion for a long period of time, the emulsion may be packed into a bag made of a laminate of a polyethylene film and an aluminum foil by 0 the pillow type packaging method together with a deoxidizer [such as Ageless (registered trademark) SA, and Ageless Z; Mitsubishi Gas Chemical Co., Ltd.].
The emulsion of the present invention can be filled into a plastic dropping bottle to use it as ear drops. In order to stably store the emulsion for a long period of time, the emulsion may be packed into a bag made of a laminate of a polyethylene film and an aluminum foil by the pillow type packaging method together with a deoxidizer [such as Ageless (registered trademark) SA, and Ageless Z; Mitsubishi Gas Chemical Co., Ltd.].
The emulsion of the present invention can be packed into a quantitative nasal nebulizer to use it as nasal drops. In order to stably store the emulsion for a long period of time, the emulsion may be packed into a bag made of a laminate of a polyethylene film and an aluminum foil by the pillow type packaging method together with a disoxidant [such as Ageless (registered trademark) SA, and Ageless Z; Mitsubishi Gas Chemical Co., Ltd.].
The emulsion of the present invention can be fed into an ampoule and the ampoule is sealed by fusion to obtain an injection (such as intravenous injection, arterial injection, hypodermic injection, intradermal injection, intramuscular injection, intraspinal injection, intraperitoneal injection, intraocular injection and the like), a liquid for internal use, an inhalation or a aerosol. The product thus obtained is fed into a suitable container selected depending on the use, such as a plastic bottle for the liquid for internal use, electric nebulizer for the inhalation, an atomizer for aerosol and the like.
The description will be made on the methods for preparing the emulsion of the present invention. Various well-known methods can be employed for preparing the emulsion of the present invention. For example, yolk lecithin, if desired a phospholipid such as phosphatidylethanolamine and an emulsifying adjuvant such as oleic acid, and FLM or CB are dissolved in a suitable organic solvent such as hexane or ethanol under stirring. Then, the solvent is evaporated under reduced pressure to prepare a thin lipid membrane. An oil and an aqueous solution prepared by dissolving a non-ionic, water-soluble cellulose derivative and optionally at least one selected from the group consisting of a chelating agent, polycarboxylic acid compounds and pharmaceutically acceptable salts thereof as well as various additives such as an antiseptic and an isotonicity agent in water, are added to the thin lipid membrane. They are vigorously stirred by agitation to conduct the pre-emulsification. The pre-emulsion thus obtained is emulsified with an ordinary emulsifying machine. After the completion of the emulsification, HCl or NaOH is added to the emulsion to adjust it to an intended pH, and thereby to obtain the O/W emulsion containing FLM or CB of the present invention. The emulsion is filtered and fed into a suitable container through a membrane filter and then sterilized to obtain the emulsion of the present invention.
When FLM is used as the active ingredient, the intended FLM-containing O/W emulsion of the present invention can be obtained by preparing an O/W emulsion comprising FLM, a phospholipid, an oil and water in the same manner as that described above, adding an aqueous solution containing a nonionic, water-soluble cellulose derivative and optionally at least one of a chelating agent, polycarboxylic acid compounds and pharmaceutically acceptable salts thereof, an antiseptic agent, an isotonicity agent and the like to the emulsion, and stirring the obtained mixture.